Summary of Work: Studies continue to determine cellular and molecular mechanisms underlying the interactions of natural/synthetic estrogenic compounds with various target tissues (developing genital tract, gonads, liver, mammary and bone tissues) resulting in permanent alterations in differentiation including dysmorphology and neoplasia. Diethylstilbestrol (DES) is used as a model estrogneic compound. In vivo studies in which DES exposure occurs during development (prenatal and/or neonatal) of the genital tract have shown various benign/malignant lesions in male/female mice similar to those reported in humans exposed to DES. Immunocytochemical/molecular genetic characteristics of the DES-induced murine tumors are being compared with those seen in human malignancies. Descendants of tumor-bearing mice have been followed for reproductive assessment and potential increased susceptibility to tumors. Accumulating data suggest that there is an increased incidence of reproductive tract tumors in the descendants of female mice developmentally exposed to DES while reproductive does not appear to be altered. The ontogeny of lactoferin (LF), complement C3, decay-accelerating factor (DAF), and the estrogen receptor (ER) in the developing reproductive tract are being mapped in vivo/in vitro to determine early estrogenic responses and the role of ER. Transgenic mice overexpressing the ER and mice expressing an altered form of the ER have been treated with DES to determine if the ER is playing a role in the induction and/or progression of uterine neoplasia. Dysmorphology in the genital tract of mice exposed to DES includes persistent gene expression of uterine LF and various growth factors including TGF-alpha and EGF which may be preneoplastic markers. Since questions remain concerning the roles of growth factors, growth inhibitors, and receptors, studies continue to identify additional human/mouse genes that characterize the different physiological states of normal/neoplastic tissue. Studies determining cell proliferation/apoptotic rates in target tissues exposed to DES have given further insights into mechanisms of DES-toxic effects. Effects of Tamoxifen and genistein on devleoping estrogen target tissues are being studied and dysmorphology/neoplastic potential compared to DES. Carcinogens in NTP rodent bioassays are being tested for estrogenic potency and compared in multiple bioassays. Sensitive markers of estrogenicity are being sought. These studies suggest a complex pattern of differentiation and development in hormone responsive target-tissues and provide important clues for mechanisms involved in the development of neoplasia.